JP6532459B2 - 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl) methyl] Novel salts of 1,3-thiazolidine-2,4-dione, preparation thereof and preparation containing the same - Google Patents

Description

The present invention relates to Formula (I):

Embedded image 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5-) The present invention relates to a novel salt of [yl] methyl] -1,3-thiazolidine-2,4-dione, a process for its preparation and a pharmaceutical composition containing it.

  3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl) methyl] The 1,3-thiazolidine-2,4-diones have very valuable pharmacological properties in the field of oncology. In fact, 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl )) [Methyl] -1,3-thiazolidine-2,4-dione has been shown to have the ability to inhibit the migration of cancer cells, from which in particular the treatment of cancer and more particularly solid metastatic tumors It is useful in Among the cancers envisaged for the treatment, without implying any limitation, cancers of colon, breast, liver, kidney, brain and esophagus, malignant melanoma, myeloma, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Mention may be made of prostate and pancreatic cancer as well as sarcomas.

  3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl) methyl] The preparation and therapeutic use of 1,3-thiazolidine-2,4-dione and its addition salts with pharmaceutically acceptable acids, more particularly the hydrochloride thereof, is described, for example, in European patent specification EP 228 1 822. ing.

  In view of the pharmaceutical value of this compound, it is important to be able to obtain the active compound in excellent yield, high purity and excellent reproducibility. It was quickly found that the hydrochloride salt used presented purification and recrystallization problems and yields which were very difficult to optimize. Furthermore, problems of reproducibility and consistency of the obtained active compounds were observed. After numerous researches, it not only combines the various advantages (in particular with regard to the purification, the reproducibility of the process to obtain it and the yield), but also the advantage that it unexpectedly significantly improves the solubility of the active compound It was possible to identify new salts that had Thus, this novel salt has all of the qualities essential to its use as a medicament both in terms of physical chemistry and pharmacokinetics.

Thus, the present invention provides 3-[(3-{[4- (4-morpholinyl-methyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5 -Yl) methyl] -1,3-thiazolidine-2,4-dione, more particularly a compound of formula (II):

Embedded image 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5-) I] Methyl] -1,3-thiazolidine-2,4-dione methanesulfonate related to the Z isomer .

FIG. 1 is an X-ray powder diffraction diagram of a compound of Example 1. 2 is a DSC diagram of the compound of Example 1.

  The present invention preferably provides 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole -5-yl) methyl] -1,3-thiazolidine-2,4-dione methanesulfonate related to the Z isomer.

This novel salt has the following advantages:
A simple and reproducible process to obtain it in excellent yield;
-Increased solubility in both water and organic solvents (which can be envisioned in purification steps such as purification to increase its purity).

  The invention also relates to 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5. -Yl) methyl] -1,3-thiazolidine-2,4-dione methanesulphonic acid salt, more particularly a process for obtaining its Z isomer, for example as described in patent specification EP 228 1 822 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5-obtained according to The present invention relates to a process characterized by using [Ill) methyl] -1,3-thiazolidine-2,4-dione as a starting material. The dione is dissolved in a solvent / water binary system, then 1 to 2 molar equivalents of methanesulfonic acid are added, and the mixture is stirred until the methanesulfonic acid salt precipitates out.

  The solvent is advantageously, for example, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, alcohols (such as methanol, ethanol and isopropanol), water, Furthermore, they may be polar solvents such as aqueous / organic mixtures of these solvents. Preferably, the solvent / water ratio will be from 0/100 to 100/0.

  A variant of the process according to the invention is 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro- 1H-Indol-5-yl) methyl] -1,3-thiazolidine-2,4-dione hydrochloride (method for obtaining this compound is described, for example, in patent specification EP 228 1 822) as starting material It consists of things. The hydrochloride is dissolved in a solvent / water binary system and the pH of the mixture is brought to 8 by addition of a base. The salts formed are removed by filtration. The filtrate is heated and then methanesulfonic acid is added. Then the temperature is slowly returned to ambient temperature and the resulting methanesulphonate is filtered off. More specifically, solvents used include acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, or alcohols (such as methanol, ethanol and isopropanol) It is a polar solvent. Preferably, the solvent / water ratio will be 70/30, more particularly 90/10. The methanesulfonic acid is used in excess, more particularly 1-2 equivalents.

  The compounds of the formula (II) according to the invention are modified under conditions: 25 ° C./60% relative humidity, 25 ° C./90% relative humidity, 30 ° C./65% relative humidity, 40 ° C./75% relative humidity, or 50 Even with ° C, they have excellent stability over time, and the compound of formula (II) does not change after 6 months.

  The invention also relates to a pharmaceutical composition comprising, as an active ingredient, a compound of the formula (II) according to the invention, more particularly the Z isomer, together with one or more inert nontoxic suitable excipients. . Among the pharmaceutical compositions according to the invention, more particularly those suitable for oral, parenteral (intravenous or subcutaneous) or intranasal administration, tablets or coated tablets, granules, sublingual agents, capsules, troches, Suppositories, creams, ointments, dermatological gels, preparations for injection, suspensions for beverages and chewing gum can be mentioned.

  A pharmaceutical dosage form comprising a compound of formula (II) according to the invention, more particularly its Z-isomer, will be used in the treatment of cancer, more particularly solid metastatic tumors. Among the cancers envisaged for the treatment, without implying any limitation, cancers of colon, breast, liver, kidney, brain and esophagus, malignant melanoma, myeloma, ovarian cancer, non-small cell lung cancer, small cell lung cancer, Mention may be made of prostate and pancreatic cancer as well as sarcomas.

  Useful doses may vary according to the nature and severity of the disorder, the route of administration and the age and weight of the patient. The dose varies from 1 mg to 1 g per day in base equivalent conversion in one or more administrations.

  The examples herein below illustrate the invention and do not limit the invention in any way.

Example 1: 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5-) [I] methyl] -1,3-thiazolidine-2,4-dione methanesulfonate (Z isomer)
3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl) methyl] Charge 1.26 g of 1,3-thiazolidine-2,4-dione to a 100 mL flask. After addition of 20 mL of a solution of acetonitrile / water (90/10), the mixture is heated at 70.degree. A solution is prepared containing 2 mL of methanesulfonic acid and 50 mL of an acetonitrile / water (90/10) mixture. When 5 mL of the resulting solution is added to the reaction mixture, it becomes clear. The solution is cooled to 20 ° C. (0.5 ° C./min, stirring at 200 rpm). After stirring overnight at ambient temperature, the title product is isolated by filtration and dried under vacuum at 40 ° C. (10 mbar).
Melting point: 270-274 ° C (melting / decomposition)

The title product is carried out on its powder diffractogram (50 mg of the compound of example 1 and makes it possible to identify the following crystallisation parameters, placed between two Kapton® films or on a support, It is characterized by a Panalytical Xpert-Pro MPD diffractometer (copper anticathode) in transmission mode with an angular range of 3 to 55 ° (2θ units), steps of 0.017 ° and loading 35.5 seconds per step:
Unit cell parameter: a = 15.0958 (5) Å, b = 18.4586 (6) Å, c = 8.8269 (2) Å, β = 9.074 (1) °, γ = 90 °
Space group: C1c1 (9)
Unit cell volume: V _{unit cell} = 2453. 37600 Å ³ .

The title product was also characterized by X-ray diffraction of a single crystal of the compound of Example 1 performed on a Rigaku XtaLAB instrument using graphite monochromic Mo-Ka radiation. The following crystallographic parameters were observed:
Unit cell parameter: a = 14.995 (4) Å, b = 18.302 (4) Å, c = 8.850 (2) Å, β = 93.528 (7) °, γ = 90 °
Space group: C1c1 (9)
Unit cell volume: V _{Unit cell} = 2424.0 (9) Å ³

  The slight differences observed in the parameters obtained using the powder are due to the temperature (−100 ° C.) used to obtain the parameters in single crystals, this temperature being between the a-axis and the b-axis Cause a contraction.

  The title product is also shown in FIG. 1, measured using a Panalytical Xpert-Pro MPD diffractometer (copper to cathode), and with an interplanar distance d, expressed as Bragg angle 2θ (° ± 0.2 And their relative intensities (expressed as a percentage of the strongest line) characterized by their X-ray powder diffractograms:

  Bragg angles 2θ (represented by ° ± 0.2) characteristic of X-ray powder diffraction patterns: 12.86; 15.13; 15.50; 17.70; 18.25; 18.71; 11; 21.46; 21.67; 21.89; 22.29; 22.58; 24.57; 25.82; 26.33.

  The compound of Example 1 was also characterized by a DSC diagram for 5-10 mg of sample loaded on a TA Instruments DSC Q1000 instrument and cooled to 0 ° C. The sample is then heated to 300 ° C. at a rate of 10 ° C./min. The resulting diagram is shown in FIG.

Example 2: 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H under denaturing conditions -Indol-5-yl) methyl] -1,3-thiazolidine-2,4-dione methanesulphonate (Z isomer) purity and stability

Example 3: 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5-) Solubility of [yl) methyl] -1,3-thiazolidine-2,4-dione methanesulfonate (Z isomer) A solution containing 140 mg of the compound obtained in Example 1 in 7 ml of water at ambient temperature for 24 hours Stir. After filtration using Acrodisc GHP 0.45 μm, the solution is analyzed by HPLC. The solubility of the compound of Example 1 is 14.7 mg / ml (or 12.1 mg / ml in terms of base equivalent). Under the same conditions, 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5-) The solubility of the hydrochloride (Z isomer) of [I] -methyl] -1,3-thiazolidine-2,4-dione is 4.3 mg / ml (or 4 mg / ml in terms of base equivalent).

Example 4: 3-[(3-{[4- (4-morpholinyl-methyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro at pH 2 (stomach pH) Dissolution Dynamics of [-1H-Indol-5-yl) methyl] -1,3-thiazolidine-2,4-dione Methanesulfonate (Z Isomer) Constant surface area solution kinetics of the product of Example 1 ( Or intrinsic dissolution kinetics) pH 2 (0.01 N at ambient temperature using a μ Diss dissolution apparatus and a 0.075 cm ² pellet prepared by compression for 2 minutes at 90 bar with a stirrer speed of 100 rpm) HCl) (10 mL). The product of Example 1 dissolves with a kinetics of 23 μg · s ⁻¹ .cm ⁻² +/− 11%. As a comparison, the dissolution kinetics of the corresponding hydrochloride salt is 1.6 μg · s ⁻¹ .cm ⁻² . As such, the methanesulfonate salt dissolves about 14 times faster than the corresponding hydrochloride salt.

Example 5: Pharmaceutical composition 1000 tablets dose 5 mg of 3- [3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-, each containing: 2,3-Dihydro-1H-indol-5-yl) methyl] -1,3-thiazolidine-2,4-dione methanesulfonate (Z isomer) (Example 1)
................................................ 5g
Wheat starch ........................................... 20 g
Corn starch ··························· 20g
Lactose ........................................... 30 g
Magnesium stearate ····························· 2g
Silica ........................................... 1g
Hydroxypropyl cellulose ·························· 2g

Claims (10)

Formula (II):

And 3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indole-5 -Yl) methyl] -1,3-thiazolidine-2,4-dione methanesulphonate Z isomer. Bragg angle 2θ (expressed in degrees ± 0.2) 12.86; 15.13; 15.50; 17.70; 18.25; 18.71; 20.11; 21.46; A crystal of the Z isomer according to claim 1, characterized by its X-ray powder diffractogram according to 67; 21.89; 22.29; 22.58; 24.57; 25.82; 26.33. 3-55 ° angle range (2θ units), 0.017 ° steps and steps on a Panalytical Xpert-Pro MPD diffractometer (copper vs. cathode) in transmission mode, making it possible to identify the following crystallographic parameters: A crystal of the Z isomer according to claim 1, characterized by the following parameters obtained starting from a powder diffraction pattern carried out at 35.5 seconds per:
Unit cell parameter: a = 15.0958 (5) Å, b = 18.4586 (6) Å, c = 8.8269 (2) Å, β = 9.074 (1) °, γ = 90 °
Space group: C1c1 (9)
Unit cell volume: V _{unit cell} = 2453. 37600 Å ³ .   3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl) -methyl ]-1, 3-thiazolidine-2,4-dione is used as a starting material, dissolved in a solvent / water binary system, to which 1 to 2 molar equivalents of methanesulfonic acid is added, and the methanesulfonic acid salt precipitates out Process for obtaining the Z isomer of formula (II) according to claim 1, characterized in that it is stirred until it is filtered off.   3-[(3-{[4- (4-morpholinylmethyl) -1H-pyrrol-2-yl] methylene} -2-oxo-2,3-dihydro-1H-indol-5-yl) -methyl ] 1,3-thiazolidine-2,4-dione hydrochloride is used as a starting material, dissolved in a solvent / water binary system, the pH is brought to 8 by addition of a base and the salt formed is filtered off 2. The method according to claim 1, characterized in that the filtrate is heated to add methanesulphonic acid and the medium is stirred to cool until the methanesulphonate precipitates and it is filtered off. Process for obtaining the Z isomer of formula (II) A Z isomer of formula (II) according to claim 1 or a crystal of a Z isomer of formula (II) according to any one of claims 2 and 3 in one or more pharmaceutically acceptable agents. Pharmaceutical composition containing in combination with an excipient.   For use in the treatment of colon, breast, liver, kidney, brain and esophagus cancer, malignant melanoma, myeloma, ovarian cancer, non-small cell lung cancer, small cell lung cancer, prostate and pancreatic cancer or sarcoma Item 7. The pharmaceutical composition according to Item 6.   A pharmaceutical composition according to claim 6, for use in combination with an anti-cancer agent selected from genotoxic agents, cytokinetics, anti-metabolites, proteasome inhibitors and kinase inhibitors. In the manufacture of a medicament for use in the treatment of cancer, the Z isomer of formula (II) according to Z isomer or any one of claims 2 and 3 of formula (II) according to claim 1 Use of crystals .   A pharmaceutical composition according to claim 6, for use in combination with radiation therapy in the treatment of cancer.